This invention relates to a method for reducing non-target levels of a diagnostic and/or therapeutic principle at a time subsequent to its injection in order to enhance the target specificity of the principle, e.g., for antibody localization for imaging and therapy.
Methods of tumor localization and therapy using labeled antibodies and antibody fragments specific to tumor-associated markers have been dislosed in Hansen et al, U.S. Pat. No. 3,927,193 and Goldenberg, U.S. Pat. Nos. 4,331,647, 4,348,376, 4,361,544, 4,460,559 and 4,460,561, and in the related applications of Goldenberg, U.S. Ser. Nos. 414,729 and 459,919, the disclosures of all of which are incorporated herein in their entirety by reference. In these patents and patent applications, subtraction techniques are disclosed for enhancing the resolution of tumor imaging by injecting a radiolabeled material capable of independent detection which can be used to subtract non-target background radiation in order to enhance the targeted specific antibody image. This can be achieved by using background agents which accumulate in the liver or spleen and can be used for subtraction of accumulated non-target label cleared by the reticuloendothelial system. An alternative subtraction technique makes use of indifferent immunoglobulin of the same or different species as that used to prepare the labeled specific antibody, the indifferent antibody being radiolabeled with a radionuclide capable of independent detection, so that the subtraction agent has substantially the same distribution kinetics as the specific antibody during the time period needed for imaging.
In both of the foregoing subtraction techniques, use of the subtraction agent involves introduction of additional radionuclides into the patient, independent detection of which facilitates a determination of the level of non-target radiation which can then be subtracted from the total radiation emmissions. This in turn permits more accurate detection of selective uptake of specific antibody by target tissues, thereby increasing the resolution of imaging methods. A disadvantage of these methods is that enhancement of resolution is achieved at the expense of introducing additional radioactive materials into the body, with all of the attendant side effects which may be produced thereby. It would be advantageous to be able to reduce the level of nontarget antibody without introduction of additional radioactivity.
It is known that specific antibodies can be entrapped in liposomes. Indeed, it was fond that humam IgM could be complexed after injection of liposomally-entrapped anti-IgM IgG in vivo, the complexes being removed by the reticuloendothelial system of the liver and/or spleen. It has also been proposed to extend this method to enhancing tumor images using radiolabeled primary markerspecific antibodies. Non-target antibody in the circulation and extravascular spaces would be cleared with liposomally-entrapped unlabeled second antibody directed against the first antibody, the clearance being effected by the reticuloendothelial system, thereby reducing the quantity of non-target radiolabeled antibody without the use of a second labeled material. It has been shown that digoxin in the circulation could be removed by administration of liposomally-entrapped anti-digoxin antibodies by means of clearance of the liposome/antigen-antibody complexes by the retriculoendothelial system. However, it was found that anti- digoxin antibody alone did not achieve this effect.
Antibodies to antigens which are produced by or associated with tumors have also been used for tumor therapy, as disclosed in the Goldenberg patents and patent applications cited hereinabove. These antibodies have been radiolabeled and/or combined with a boron-containing addend capable of activation with thermal neutrons. In these therapeutic techniques, it would be advantageous to be able to reduce the level of non-target antibody to enhance the specificity of localization of the therapeutic agent. It would also be desirable, although it has not been disclosed, to extend imaging and therapy beyond the use of antibodies to tumor-associated markers to encompass antibodies to antigens produced by or associated with infectious lesions of all sorts, and to the use of antibodies labeled with labels other than radionuclides.